Regulation of Apoptosis in the Testis

  • Tim L. Beumer
  • Dirk G. De Rooij
Part of the Serono Symposia USA book series (SERONOSYMP)


It has become clear that germ cell death in the testis, inducible by a variety of rather diverse factors and circumstances, invariably proceeds via a process resembling that of active cell death, called apoptosis as described for other cell types (for review, see 1). Apoptosis may take place following several pathways, probably dependent on the kind of apoptotic stimulus the cells get. The regulation of apoptosis has appeared to be of increasing complexity. Apoptosis can be divided into phases (2), with the various apoptosis regulators acting during different phases of the apoptotic pathway. In the first phase, the cell becomes affected by an apoptotic stimulus. For germ cells, many factors have been shown to directly or indirectly act as an apoptotic stimulus, such as temperature, hormone levels, and xenobiotic agents like radiation and cytostatic drugs (1). In the second phase, the cell detects the apoptotic stimulus, whereafter, in phase three, the cell responds. Finally, at phase four, the cell completely degrades. Proteins involved in apoptosis regulation in each of these phases were shown to be expressed in the testis, leading to an initial understanding of which apoptotic pathways are present in germ cells. As the factors involved in the first phase of apoptosis induction have already been described in this volume (1), only the factors that regulate other phases of apoptosis will be described in this chapter, with the emphasis on those already known to be expressed in the testis (Table 19.1).


Germ Cell Sertoli Cell Mouse Testis Apoptotic Stimulus Human Testis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Russell LD. Cell loss during spermatogenesis: apoptosis or necrosis?. In: Hamamah S, Mieusset R, Olivenes F, Jouannet P, Frydman R, editors. Male sterility for motility disorders: etiological factors and treatment. New York: Springer, 1998.Google Scholar
  2. 2.
    Vaux DL, Strasser A. The molecular biology of apoptosis. Proc Natl Acad Sci USA 1996;93:2239–44.PubMedCrossRefGoogle Scholar
  3. 3.
    Levine AJ. P53, the cellular gatekeeper for growth and division. Cell 1997;88:323–31.PubMedCrossRefGoogle Scholar
  4. 4.
    Chernova OB, Chernov MV, Agarwal ML, Taylor WR, Stark GR. The role of p53 in regulating genomic stability when DNA and RNA synthesis are inhibited. Trends Biochem Sci 1995;20:431–34.PubMedCrossRefGoogle Scholar
  5. 5.
    Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 1992;89:7491–95.PubMedCrossRefGoogle Scholar
  6. 6.
    Zölzer F, Hillebrandt S, Streffer C. Radiation induced G1-block and p53 status in six human cell-lines. Radiother Oncol 1995;37:20–28.PubMedCrossRefGoogle Scholar
  7. 7.
    Guillouf C, Rosselli F, Krishnaraju K, Moustacchi E, Hoffman B, Liebermann DA. P53 involvement in control of G2 exit of the cell cycle: role in DNA damage-induced apoptosis. Oncogene 1995;10:2263–70.PubMedGoogle Scholar
  8. 8.
    Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995;80:293–99.PubMedCrossRefGoogle Scholar
  9. 9.
    Kastan MB, Onyekwer O, Sidransky D, Vogelstein B, Craig RW. Participation of p53 protein in the cellular response. Cancer Res 1992;51;6304–11.Google Scholar
  10. 10.
    El-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993;75:817–25.PubMedCrossRefGoogle Scholar
  11. 11.
    Almon E, Goldfinger N, Kapon A, Schwartz D, Levine AJ, Rotter V. Testicular tissue-specific expression of the p53 suppressor gene. Dev Biol 1993;156:107–16.PubMedCrossRefGoogle Scholar
  12. 12.
    Schwartz D, Goldfinger N, Rotter V. Expression of p53 protein in spermatogenesis is confined to the tetraploid pachytene primary spermatocytes. Oncogene 1993;8:1487–94.PubMedGoogle Scholar
  13. 13.
    Sjöblom T, LÄhdetie J. Expression of p53 in normal and gamma-irradiated rat testis suggests a role for p53 in meiotic recombination and repair. Oncogene 1996;12:2499–505.PubMedGoogle Scholar
  14. 14.
    Rotter V, Schwartz D, Almon E, et al. Mice with reduced levels of p53 protein exhibit the testicular giant-cell degenerative syndrome. Proc Natl Acad Sci USA 1993;90:9075–79.PubMedCrossRefGoogle Scholar
  15. 15.
    Beumer TL, Roepers-Gajadien HL, Gademan IS, Rutgers DH, de Rooij DG. P21(ciPi/wafiup) expression in the mouse testis before and after X-irradiation. Mol Reprod Dev 1997;47:240–47.PubMedCrossRefGoogle Scholar
  16. 16.
    Donehower LA, Harvey M, Slagle BL, et al. Mice deficient for p53 are developmen-tally normal but susceptible to spontaneous tumours. Nature 1992;356:215–21.PubMedCrossRefGoogle Scholar
  17. 17.
    Van Beek MEAB, Davids JAG, van de Kant HJG, de Rooij DG. Response to fission neutron irradiation of spermatogonial stem cells in different stages of the cycle of the seminiferous epithelium. Radiât Res 1984;97:556–69.PubMedCrossRefGoogle Scholar
  18. 18.
    Hendry JH, Adeeko A, Porten CS, Morris ID. P53 deficiency produces fewer regenerating spermatogenic tubules after irradiation. Int J Radiât Biol 1996;70:677–82.PubMedCrossRefGoogle Scholar
  19. 19.
    West A, Lähdetie J. P21WAF1 expression during spermatogenesis of the normal and X-irradiated rat. Int J Radiât Biol 1997;73:283–91.Google Scholar
  20. 20.
    Korsmeyer SJ. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 1995;270:96–99.PubMedCrossRefGoogle Scholar
  21. 21.
    Kroemer G. The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nature Med 1997;3:614–20.PubMedCrossRefGoogle Scholar
  22. 22.
    Rodriguez I, Ody C, Araki K, Garcia I, Vassalli P. An early and massive wave of germinal cell apoptosis is required for the development of functional spermatoge-nesis. EMBO J 1997;16:2262–70.PubMedCrossRefGoogle Scholar
  23. 23.
    De Rooij DG, Lok D. The regulation of the density of spermatogonia in the seminiferous epithelium of the Chinese hamster. II. Differentiating spermatogonia. Anat Rec 1987;217:131–36.PubMedCrossRefGoogle Scholar
  24. 24.
    Furuchi T, Masuko K, Nishimune Y, Obinata M, Matsui Y. Inhibition of testicular germ cell apoptosis and differentiation in mice misexpressing Bcl-2 in spermatogonia. Development 1996;122:1703–9.PubMedGoogle Scholar
  25. 25.
    Krajewski S, Bodrug S, Krajewska M, et al. Immunohistochemical analysis of Mcl-1 protein in human tissues. Differential regulation of Mcl-1 and Bcl-2 production suggests a unique role for Mcl-1 in control of programmed cell death in vivo. Am J Pathol 1995;146:1309–19.PubMedGoogle Scholar
  26. 26.
    Knudson CM, Tung KSK, Tourtelotte WG, Brown GAJ, Korsmeyer SJ. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 1996;270:96–99.CrossRefGoogle Scholar
  27. 27.
    Skinner MK, Moses HL. Transforming growth factor beta gene expression and action in the seminiferous tubule: peritubular cell-Sertoli cell interaction. Mol Endocrinol 1989;3:625–34.PubMedCrossRefGoogle Scholar
  28. 28.
    Watrin F, Scotto L, Assoian RK, Wolgemuth DJ. Cell lineage specificity of expression of the murine transforming growth factor beta 3 and transforming growth factor beta 1 genes. Cell Growth Differ 1991;2:77–83.PubMedGoogle Scholar
  29. 29.
    Teerds KJ, Dorrington JH. Localization of transforming growth factor beta 1 and beta 2 during testicular development in the rat. Biol Reprod 1993;48:40–45.PubMedCrossRefGoogle Scholar
  30. 30.
    Chen RH, Chang TY. Involvement of caspase family proteases in transforming growth factor-factor-beta-induced apoptosis. Cell Growth Differ 1997;8:821–27.PubMedGoogle Scholar
  31. 31.
    Hipp ML, Bauer G. Intercellular induction of apoptosis in transformed cells does not depend on p53. Oncogene 1997;15:791–97.PubMedCrossRefGoogle Scholar
  32. 32.
    Xiao BG, Bai XF, Zhang GX, Link H. Transforming growth factor-beta 1 induces apoptosis of rat microglia without relation to bcl-2 oncoprotein expression. Neurosci Lett 1997;226:71–74.PubMedCrossRefGoogle Scholar
  33. 33.
    Oursler MJ, Cortese C, Keeting P, et al. Modulation of transforming growth factor-beta production in normal human osteoblast-like cells by 17 beta-estradiol and parathyroid hormone. Endocrinology 1991;129:3313–20.PubMedCrossRefGoogle Scholar
  34. 34.
    Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nature Med 1996;2:1132–36.PubMedCrossRefGoogle Scholar
  35. 35.
    Landstrom M, Eklov S, Colosetti P, et al. Estrogen induces apoptosis in a rat prostatic adenocarcinoma: association with an increased expression of TGF-beta 1 and its type-I and type-II receptors. Int J Cancer 1996;67:573–79.PubMedCrossRefGoogle Scholar
  36. 36.
    Chen H, Tritton TR, Kenny N, Asher M, Chiu JF. Tamoxifen induces TGF-beta 1 activity and apoptosis of human MCF-7 breast cancer cells in vitro. J Cell Biochem 1996;61:9–17.PubMedCrossRefGoogle Scholar
  37. 37.
    Sanderson N, Factor V, Nagy P, et al. Hepatic expression of mature transforming growth factor beta-1 in transgenic mice results in multiple tissue lesions. Proc Natl Acad Sei USA 1995;92:2572–76.CrossRefGoogle Scholar
  38. 38.
    Sanberg PR, Saporta S, Boriongan CV, Othberg AI, Allen RC, Cameron DF. The testis-derived cultured Sertoli cell as a natural Fas-L secreting cell for immunosup-pressive cellular therapy. Cell Transplant 1997;6:191–93.PubMedCrossRefGoogle Scholar
  39. 39.
    Lee J, Riehburg JH, Younkin SC, Boekelheide K. The Fas system is a key regulator of germ cell apoptosis in the testis. Endocrinology 1997;138:2081–88.PubMedCrossRefGoogle Scholar
  40. 40.
    Bellgrau D, Gold D, Selawry H, Moore J, Franzusoff A, Duke RC. A role for CD95 ligand in preventing graft rejection. Nature 1995;377:630–32.PubMedCrossRefGoogle Scholar
  41. 41.
    Xerri L, Devilard E, Hassoun J, Mawas C, Birg F. Fas ligand is not only expressed in immune privileged human organs but is also coexpressed with Fas in various epithelial tissues. Mol Pathol 1997;50:87–91.PubMedCrossRefGoogle Scholar
  42. 42.
    Ohta Y, Nishikawa A, Fukazawa Y, et al. Apoptosis in adult mouse testis induced by experimental eryptorchidism. Acta Anat 1996;157:195–204.PubMedCrossRefGoogle Scholar
  43. 43.
    Heiskanen P, Billig H, Toppari J, et al. Apoptotic cell death in the normal and the cryptorchid human testis: the effect of human chorionic gonadotropin on testicular cell survival. Pediatr Res 1996:40:351–56.PubMedCrossRefGoogle Scholar
  44. 44.
    Dunkel L, Hirvonen V, Erkkilä K. Clinical aspects of male germ cell apoptosis during testis development and spermatogenesis. Cell Death Differ 1997;4:171–79.PubMedCrossRefGoogle Scholar
  45. 45.
    Li LH, Wine RN, Chapin RE. 2-Methoxyacetic acid (MAA)-induced spermatocyte apoptosis in human and rat testes: an in vitro comparison. J Androl 1996;17:538–49.PubMedGoogle Scholar
  46. 46.
    Salvesen GS, Dixit VM. Caspases: intracellular signaling by proteolysis. Cell 1997;91:443–46.PubMedCrossRefGoogle Scholar
  47. 47.
    Keane KM, Giegel DA, Lipinski WJ, Callahan MJ, Shivers BD. Cloning, tissue expression and regulation of rat interleukin 1 beta converting enzyme. Cytokine 1995;7:105–10.PubMedCrossRefGoogle Scholar
  48. 48.
    Gaultier C, Levacher C, Avallet O, et al. Immunohistochemical localization of transforming growth factor-beta 1 in the fetal and neonatal rat testis. Mol Cell Endocrinol 1994;99:55–61.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Tim L. Beumer
  • Dirk G. De Rooij

There are no affiliations available

Personalised recommendations